Compounds of formula: wherein R1 is hydrogen or a lower alkyl radical and n is 4, 5, or 6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.
U.S. Ser. No. 09/485,382 filed Feb. 8, 2000 teaches in part compounds of Formula I: or a pharmaceutically acceptable salt thereof wherein R is hydrogen or a lower alkyl; and R1 to R8 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, —CO2H, —CO2R15, —CH2CO2H, —CH2CO2R15, —OR15 wherein R15 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and R1 to R8 are not simultaneously hydrogen. This patent application is hereby incorporated by reference.
U.S. Pat. No. 5,929,116 describes endothelin antagonists of formulas: wherein                R1 is —X(CH2)nAr;        R2 is Ar;        P1 is —X(CH2)nR8;        P2 is —X(CH2)nR8, or —XR9Y;        R3 and R5 are independently hydrogen, R11, OH, C1-8 alkoxy, S(O)qR11, N(R6)2, Br, F, I, Cl, CF3, NHCOR6, —R11CO2R7, —XR9—Y, or —X(CH2)nR8 wherein each methylene group within —X(CH2)nR8 may be unsubstituted or substituted by one or two —(CH2)nAr groups;        R4 is hydrogen, R11, OH, C1-5 alkoxy, S(O)qR11, N(R6)2, —X(R11), Br, F, I, Cl, or NHCOR6 wherein the C1-5 alkoxy may be unsubstituted or substituted by OH, methoxy, or halogen;        R6 is independently hydrogen or C1-4 alkyl;        R7 is independently hydrogen, C1-6 alkyl, or (CH2)nAr;        R8 is hydrogen, R11, CO2R7, PO3H2, SO2NR7R11, NR7SO2R11, P(O)(OH)R7, CN, —C(O)N(R6)2, tetrazole, or OR6;        R9 is C1-10 alkyl, C2-10 alkenyl, or phenyl, all of which may be unsubstituted or substituted by one or more OH, N(R6)2, COOH, >C═O, halogen, or XC1-5 alkyl;        R10 is R3 or R4;        R11 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(R6)2, or halogen;        X is (CH2)n, O, NR6, or S(O)q;        Y is CH3 or X(CH2)nAr;        Ar is:          naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more R3 or R4 groups;        A is >C═O, or [C(R6)2]m;        B is —CH2— or —O—;        Z1, Z2, Z3, and Z4 are independently hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, OH, C1-8 alkoxy, S(O)qC1-8 alkyl, N(R6)2, Br, F, I, Cl, NHCOR6, —X(CH2)nR8, XR9Y, phenyl, benzyl, or C3-6 cycloalkyl wherein the C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl may be optionally substituted by COOH, OH, CO(CH2)nCH3, CO(CH2)nCH2N(R6)2, or halogen;        q is zero, one, or two;        n is an integer from 0 to 6;        m is 1, 2, or 3;        and the dotted line in Formula (I) indicates the optional presence of a double bond; or a pharmaceutically acceptable salt thereof; provided that                    when the optional double bond is present, there is only one R10, there is no P1, and P2 is not NR6R9Y;            X is not NR6, and Z3 is not OH or N(R6)2 in Formula (III);            Z1 and Z3 are not OH, N(R6)2, or Iodine in Formula (II);            when the optional double bond is present in Formula (I) and X—R2 is attached to the double bond, X is not NR6;            when the optional double bond is present in Formula (I) and R1 is attached directly to the double bond, R1 is not NR6Ar;            when R3, R5, Z1, Z2, or Z3 is X(CH2)nR8 and n is not zero, X is oxygen or NR6 when R8 is OR6 or CO2H.                        
Also included in the invention are pharmaceutically acceptable salts of the active compounds.
Most or all of the desired pharmacological activity of a compound comprised of two or more stereoisomers frequently resides in just one of the stereoisomers. The other stercoisomer(s) typically is inactive at best or exhibits undesirable side effects such as, for example, toxicity. Therefore where a compound is comprised of two or more stereoisomers, it is important, and sometimes mandatory, to develop a method of selectively preparing the beneficial stereoisomer in a form that is free from, or almost free from, contamination by the other inactive or harmful stercoisomer(s). However, usually it is very difficult to discover a method for the preparation of a beneficial stereoisomer in a form that is free from, or almost free from, contamination by the other inactive or harmful stereoisomer(s). Unexpectedly, we have invented novel preparations of certain important 3-substituted cyclopentyl-containing, amino acid analogs of gabapentin, a marketed anticonvulsant, which provide the desirable stereoisomers with a high degree of stereochemical purity.
None of the above teach the synthesis of the instant invention.